Methods, systems, and devices for pairing vagus nerve stimulation with motor therapy in stroke patients

ABSTRACT

A method of treating motor deficits in a stroke patient, comprising assessing a patient&#39;s motor deficits, determining therapeutic goals for the patient, based on the patient&#39;s motor deficits, selecting therapeutic tasks based on the therapeutic goals, performing each of the selected therapeutic tasks repetitively, observing the performance of the therapeutic tasks, initiating the stimulation of the vagus nerve manually at approximately a predetermined moment during the performance of the therapeutic tasks, stimulating the vagus nerve of the patient during the performance of the selected therapeutic tasks, and improving the patient&#39;s motor deficits.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. patent application Ser. No.14/252,727, filed Apr. 14, 2014, which is a Continuation application ofU.S. application Ser. No. 13/651,349, filed Oct. 12, 2012, now U.S. Pat.No. 8,700,145, issued Apr. 15, 2014, which claims priority to thebenefit of U.S. Provisional Patent Application No. 61/699,470, filedSep. 11, 2012, U.S. Provisional Patent Application No. 61/614,369, filedMar. 22, 2012, U.S. Provisional Patent Application No. 61/598,185, filedFeb. 13, 2012, U.S. Provisional Patent Application No. 61/558,287, filedNov. 10, 2011, and U.S. Provisional Patent Application No. 61/627,532,filed Oct. 13, 2011. This application is also a Continuation-In-Part ofU.S. patent application Ser. No. 13/095,570, filed Apr. 27, 2011, whichclaims the benefit of U.S. Provisional Patent Application No.61/328,621, filed Apr. 27, 2010 and which is a Continuation-In-Part ofU.S. patent application Ser. No. 12/485,040, filed Jun. 15, 2009, whichclaims the benefit of: U.S. Provisional Patent Application No.61/077,648, filed Jul. 2, 2008; U.S. Provisional Patent Application No.61/078,954, filed Jul. 8, 2008; U.S. Provisional Patent Application No.61/086,116, filed Aug. 4, 2008; and U.S. Provisional Patent ApplicationNo. 61/149,387, filed Feb. 3, 2009. All of these applications areincorporated herein by reference as if reproduced in their entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not applicable.

REFERENCE TO A MICROFICHE APPENDIX

Not applicable.

BACKGROUND

Stroke is a leading cause of adult disability in the United States, withupper motor deficits being the primary result of the disability. Thesemotor disabilities greatly affect quality of life for the patient andtheir loved ones. In addition, the loss of motor function exacts afinancial toll on the healthcare system of nearly $70 billion yearly.Patients with hemiplegia or hemiparesis generally regain walking withoutthe use of an assistive device while only half to one-third of patientsregain some degree of use of their upper extremity, even after intensiverehabilitation therapy. The severe functional impairment affectsoccupational performance, and as a result, few stroke victims are ableto return to work. Upper limb motor disabilities from stroke have anunfavorable effect on the activities of daily living criticallyaffecting the quality of life for the stroke victim as well as familymembers and caregivers.

Physical rehabilitation can result in significant improvements in motoroutcomes after stroke. Improvements in recovery of upper extremityfunction have also been reported for electromyographic feedback, motorimagery, robotics, and repetitive task practice, though large scaleclinical trials have yet to be implemented. Unfortunately for mostpatients, the gains are not enough to have a large impact on dailyliving. Further, current rehabilitative therapies, such asconstraint-induced movement therapy, are restricted to individuals withmild to moderate deficits. Few options are available for those strokesurvivors with moderate to severe deficits. Therefore, there is still atremendous need for methods that improve recovery of function evenfurther.

To enhance recovery further, adjuvant therapies have been tried. Forexample, amphetamines can be effective at enhancing recovery of motorabilities beyond that seen with physical rehabilitation alone; however,even the positive results for motor outcomes are only incremental, andamphetamine use has many well-known side effects. Several small,randomized controlled trials have shown that epidural stimulationsignificantly improves motor recovery in animal models and in humanstroke survivors. Unfortunately, the method requires brain surgeryassociated with the potential for significant complications and is notlikely to reach widespread clinical use in stroke patients. Also, arecent randomized clinical trial failed to demonstrate improved efficacycompared with intensive physical rehabilitation.

Less invasive methods for cortical stimulation have also been combinedwith physical rehabilitation. Again, however, while real gains infunction are observed, the gains are modest, for the most part. Thus, agreat need still exists for a method to improve motor function further.

Current rehabilitation techniques do not sufficiently restore lostfunction in many individuals. Statistically significant improvements tomotor deficits can be induced even several months after stroke. However,these improvements do not consistently improve quality of life for thevast majority of patients and their caretakers, thus greaterimprovements in motor skills are needed following rehabilitation.

Motor therapies typically involve practicing either fine motor or grossmotor skills. Repetition is generally the mechanism of the therapies. Insome variations, such as constraint therapy and mirror therapy, othermechanisms are engaged.

Some examples of typical motor therapies may be actions such as:squeezing a dynamometer, turning on/off a light switch, using a lock andkey, opening and closing a door by twisting or depressing differentdoorknobs, flipping cards, coins and other objects over, placing lightand heavy objects at different heights, moving pegs to hole and removepegs from hole, lifting a shopping basket/briefcase, drawing geometricshapes, dressing, typing, reaching and grasping light and heavy objects,grasping and lifting different (size, shape, and texture) objects, doinga precision grasp, writing, drawing connect the dots, opening andclosing a jar or medication bottle, lifting an empty and full cup/glass,using feeding utensils, cutting food, stirring liquids, scooping,pouring a glass of water with the paretic hand; or using the paretichand to stabilize the glass and pouring with the good hand, picking anobject and bring to target, using a spray can, cutting with scissors, orbrushing teeth/hair.

U.S. Pat. No. 6,990,377 (Gliner, et al.) describes a therapy to treatvisual impairments. The therapy includes presenting various types ofvisual stimuli in conjunction with stimulation of the visual cortex. Thetherapy described in Gliner does not control the timing relationship ofthe stimuli and the stimulation.

U.S. Patent Application Publication 2007/1079534 (Firlik, et al.)describes a therapy having patient interactive cortical stimulationand/or drug therapy. The therapy has patients performing tasks,detecting patient characteristics and modifying the stimulationdepending on the detected patient characteristics. The therapy describedin Firlik does not control the timing relationship between the tasks andthe cortical stimulation.

It is common in the prior art to suggest that stimulation of the cortex,the deep brain, the cranial nerves and the peripheral nerves are somehowequivalent or interchangeable to produce therapeutic effects. Despitethese blanket statements, stimulation at different parts of the nervoussystem is not equivalent. It is generally understood that the vagusnerve is a nerve that performs unique functions through the release of awide array of neuromodulators throughout the brain. To generate certainkinds of plasticity, the timing of the stimulation of the vagus nerve iscritical in producing specific therapeutic effects.

U.S. Pat. No. 6,104,956 (Naritoku, et al.) is representative of workdone using vagus nerve stimulation (VNS) to treat a variety ofdisorders, including epilepsy, traumatic brain injury, and memoryimpairment. The VNS is delivered without reference to any other therapy.To improve memory consolidation, VNS is delivered several minutes aftera learning experience. Memory consolidation is unrelated to the presenttherapy for treating motor deficits.

SUMMARY

For purposes of summarizing the disclosure, certain aspects, advantages,and novel features of the disclosure have been described herein. It isto be understood that not necessarily all such advantages may beachieved in accordance with any particular embodiment of the disclosure.Thus, the disclosure may be embodied or carried out in a manner thatachieves or optimizes one advantage or group of advantages as taughtherein without necessarily achieving other advantages as may be taughtor suggested herein.

In an embodiment, the disclosure includes a method of treating motordeficits in a stroke patient, comprising assessing a patient's motordeficits, determining therapeutic goals for the patient, based on thepatient's motor deficits, selecting therapeutic tasks based on thetherapeutic goals, performing each of the selected therapeutic tasksrepetitively, stimulating the vagus nerve of the patient during theperformance of the selected therapeutic tasks, and improving thepatient's motor deficits.

In a second embodiment, the disclosure includes a method of treatingmotor deficits in a stroke patient, comprising assessing a patient'smotor deficits, determining therapeutic goals for the patient, based onthe patient's motor deficits, selecting therapeutic tasks based on thetherapeutic goals, performing each of the selected therapeutic tasksrepetitively, observing the performance of the therapeutic tasks,initiating the stimulation of the vagus nerve manually at approximatelya predetermined moment during the performance of the therapeutic tasks,stimulating the vagus nerve of the patient during the performance of theselected therapeutic tasks, and improving the patient's motor deficits.

In a third embodiment, the disclosure includes a method of treatingmotor deficits in a stroke patient, comprising assessing a patient'smotor deficits, determining therapeutic goals for the patient, based onthe patient's motor deficits, selecting therapeutic tasks based on thetherapeutic goals, performing each of the selected therapeutic tasksrepetitively, detecting the performance of the therapeutic task,automatically initiating vagus nerve stimulation at a predeterminedmoment during the detected performance of the therapeutic task,stimulating the vagus nerve of the patient during the performance of theselected therapeutic tasks, and improving the patient's motor deficits.

In a fourth embodiment, the disclosure includes a system for providingtherapy for a motor deficit, comprising, an implantable stimulationsystem including an implantable pulse generator (IPG), lead andelectrodes to stimulate a patient's vagus nerve, a clinical controllerwith stroke therapy software, an external communication device tocommunicate between the clinical controller and the implantablestimulation system, and a manual input device, coupled to the clinicalcontroller, wherein the manual input device is engaged duringperformance of a therapeutic task causing the clinical controller tosend a signal using the external communication device to the implantablestimulation system, so that a patient's vagus nerve is stimulated duringthe performance of the therapeutic task.

In a fifth embodiment, the disclosure includes a system for providingautomated therapy for a motor deficit, comprising, an implantablestimulation system including an IPG, lead and electrodes to stimulate apatient's vagus nerve, a clinical controller with stroke therapysoftware, an external communication device to communicate between theclinical controller and the implantable stimulation system, and a motiondetection system, coupled to the clinical controller, wherein the motiondetection system detects performance of a therapeutic task and at apredetermined time during the therapeutic task causing the clinicalcontroller to send a signal using the external communication device tothe implantable stimulation system, so that a patient's vagus nerve isstimulated during the performance of the therapeutic task.

These and other features may be more clearly understood from thefollowing detailed description taken in conjunction with theaccompanying drawings and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of this disclosure, reference is nowmade to the following brief description, taken in connection with theaccompanying drawings and detailed description, wherein like referencenumerals represent like parts.

FIG. 1 is a flowchart depicting a task selection and therapy parameterselection process for a paired-VNS motor therapy, in accordance with anembodiment;

FIG. 2 is a flowchart depicting a setup and administration process for apaired-VNS motor therapy, in accordance with an embodiment;

FIG. 3 is a flowchart depicting another setup and administration processfor an automated paired-VNS motor therapy protocol, in accordance withan embodiment;

FIG. 4 is a graph depicting the timing of a therapeutic motion andexamples of possible stimulation timing variations for paired VNS;

FIG. 5 depicts an implantable vagus nerve stimulation system, in situ,in accordance with an embodiment;

FIG. 6 is a functional block diagram depicting a paired-VNS motortherapy system including a manual VNS switch, in accordance with anembodiment;

FIG. 7 is a functional block diagram depicting an automated paired-VNSmotor therapy system, in accordance with an embodiment;

FIG. 8 is a screenshot of an initial interface screen, in accordancewith an embodiment;

FIG. 9 is a screenshot of a therapy information screen, in accordancewith an embodiment;

FIG. 10 is a screenshot of a stimulation parameter input screen, inaccordance with an embodiment;

FIG. 11 is a screenshot of a therapy input screen, in accordance with anembodiment;

FIG. 12 is a screenshot of an IPG parameter input screen, in accordancewith an embodiment;

FIG. 13 is a screenshot of a therapy delivery screen, in accordance withan embodiment;

FIG. 14 is a schematic diagram of an automated pairing system, inaccordance with an embodiment; and

FIG. 15 is a screenshot of an automated therapy screen, in accordancewith an embodiment.

DETAILED DESCRIPTION

It should be understood at the outset that although an illustrativeimplementation of one or more embodiments are provided below, thedisclosed systems and/or methods may be implemented using any number oftechniques, whether currently known or in existence. The disclosureshould in no way be limited to the illustrative implementations,drawings, and techniques illustrated below, including the exemplarydesigns and implementations illustrated and described herein, but may bemodified within the scope of the appended claims along with their fullscope of equivalents. The present application describes severalembodiments, and none of the statements below should be taken aslimiting the claims generally.

Where block diagrams have been used to illustrate the embodiments, itshould be recognized that the physical location where describedfunctions are performed are not necessarily represented by the blocks.Part of a function may be performed in one location while another partof the same function is performed at a distinct location. Multiplefunctions may be performed at the same location. In a functional blockdiagram, a single line may represent a connection, in general, or acommunicable connection, particularly in the presence of a double line,which may represent a power connection. In either case, a connection maybe tangible, as in a wire, or radiated, as in near-field communication.An arrow may typically represent the direction of communication or poweralthough should not be taken as limiting the direction of connectedflow.

Therapy

VNS is paired with a motor therapy by providing the stimulation at sometime during the motor therapy, for example, the beginning of the motion.Because the cortical plasticity is generated by the stimulation for ashort time period, as short as a few seconds, the VNS should be providedso that most of the VNS is during the motions that constitute thetherapy.

With reference to FIG. 1, a flowchart 100 depicts a task selection andtherapy parameter selection process for a paired-VNS motor therapy 100,in accordance with an embodiment. The process 100 begins with a patientevaluation at 102. The patient evaluation may include a standard medicalevaluation, medical history, and assessment of the patient's motordeficit. Persons of ordinary skill in the art are aware of otherinformation that can be included in a patient evaluation. The patient'smotor deficit or handicap may be assessed using standard motor deficitassessment criteria, such as Fugl-Meyer, Barthel Index, Box and BlockTest, Canadian Occupation Performance Measure (COPM), FunctionalIndependence Measure (FIM), Motor Assessment Scale (MAS), ActionResearch Arm Test (ARAT), Modified Rankin Scale, Nine hole peg test, NIHStroke scale, Stroke Impact Scale (SIS) or any other appropriateassessment measures.

The process 100 may continue with setting the therapeutic goals at 104.Therapeutic goals may include such things as tying shoes, unlockingdoors, eating, or performing other basic life tasks. Persons of ordinaryskill in the art are aware of other types of goals.

Taking into consideration the therapeutic goals, a set of tasks areselected at 106 that either address specific muscle groups necessary toachieve the therapeutic goals, mimic the basic life tasks, or mimic someportion of those tasks. For example, if the goal is to be able to unlocka door, then the task of inserting a key and turning the key in a lockmay be selected as a task. On the other hand, if the patient issuffering from more serious disabilities in this regard, then the taskof reaching and grasping an object may be selected, as a first steptoward the task of unlocking a door.

Tasks may include: Reach and grasp; Lift objects from table;Circumduction and bimanual tasks (mainly involving wrist and distaljoints); Stacking objects; Slide credit card in slot; Turning on and offlight switch; Squeezing objects; Writing; Typing; Stirring liquid in abowl (bimanual); Dial a cell phone (bimanual); Fold towels or clothes(bimanual); Wear a belt; Tying shoelaces; Eating; Brushing teeth;Combing hair.

Each of the tasks is defined with a spectrum of levels. The task ofmoving a weight, for example, may include smaller weights and largerweights. Given a patient's abilities and the therapeutic goals, theinitial task level is selected at 108. The patient may begin performingthe task at the selected level. As the therapy proceeds, the level ofthe task may be changed to reflect changes in the patient's ability toperform the task. If a patient becomes adept at performing a task at theselected level, the level may be increased. If the patient struggles toperform the task at a given level, the level may be decreased.

Each task may be repeated many times. In a typical therapy, a task maybe repeated from about 30 to about 50 times in a session. The number ofrepetitions for each task is selected at 110. The stimulation parametersfor the vagus nerve stimulation, such as the amplitude, pulse width, theduration of the pulse train, frequency, and train period are selected at112.

With reference to FIG. 2, a setup and therapy delivery process 200 isshown. The physical items necessary for a selected task may be setup inthe appropriate therapy space at 202. The task and task parameters, suchas what counts as success, are explained to the patient at 204. The taskdelivery software is used to control the delivery of stimulations and torecord data at 206. When the patient is instructed that the therapy hasbegun, the patient performs the first selected task at 208, inaccordance with the instructions given. At approximately a determinedpoint in the performance of the task, the manual input device is used tocause the vagus nerve of the patient to be stimulated at 210. Typically,the vagus nerve is stimulated with a 500 millisecond pulse train atapproximately 0.8 milliamperes. The 500 millisecond duration has beenselected as sufficient to generate directed plasticity. Experiments haveshown that a 500 millisecond stimulation generates directed plasticitythat lasts less than 8 seconds. While longer pulse trains may beeffective, the shorter duration is typically preferred because theshorter stimulation leads to less side effects. Following stimulation at212, there is a period of non-stimulation, which may be at least as longas the preceding period of stimulation. The period of non-stimulationmay be a safety measure and may be part of the therapeutic process. Whenthe task has been completed, the task level may be evaluated at 214, todetermine if the task level is too simple or too advanced for thepatient. The task level may be changed at this point, as appropriate.The patient then performs the task again at 208 until the task has beenrepeated a predetermined number of times.

With reference to FIG. 3, a setup and automated therapy process 300 isshown. The physical items necessary for a selected task may be setup inthe appropriate therapy space at 302. The setup may include initiatingsoftware to administer the automation. The task and the task parameters,such as what counts as success, are explained to the patient at 304. Thetask delivery software is used to control the delivery of stimulationsand to record data at 306. When the patient is instructed that thetherapy has begun, the patient performs the first selected task at 308,in accordance with the instructions given. A clinical control devicedetects task performance at 310. Cameras or other sensors may be usedfor to detect the patient's movements. At a determined point in theperformance of the task, the control device causes the vagus nerve ofthe patient to be stimulated at 312. Following stimulation, there is aperiod of non-stimulation at 314, which may be at least as long as thepreceding period of stimulation. The period of non-stimulation may be asafety measure and may be part of the therapeutic process. When the taskhas been completed, the task level may be evaluated at 316, to determineif the task level is too simple or too advanced for the patient. Thetask level may be changed at this point, as appropriate. The patientthen performs the task again at 308 until the task has been repeated apredetermined number of times.

With reference to FIG. 4, a graph depicts the timing of the therapeutictask and examples of vagus nerve stimulation timing. Before a motionbegins, the patient forms a mental intention and soon after, the motionbegins. The task may typically include a series of motions. For example,a task may include, reaching, grasping, moving, releasing, andreturning. Between each of these motions is a transition point or stepthat may be used to time the stimulation. Finally, the motion ends.

The vagus nerve stimulation may be effectively delivered at varioustimes during the therapeutic task. For example, line a shows a vagusnerve stimulation given after the intention to move is formed and beforethe motion begins. Line b shows a vagus nerve stimulation deliveredafter the motion begins. Line c shows a vagus nerve stimulationdelivered after a first transition point or step in the therapeutictask. Line d shows a vagus nerve stimulation delivered after a secondtransition point or step in the therapeutic task. Line e shows a longervagus nerve stimulation delivered between the time the motion starts andshortly after the motion ends. The extended stimulation duration shownat line e may be a single long pulse train or a series of half-secondpulse trains. Line f shows three vagus nerve stimulations deliveredduring the therapeutic task, after the motion begins, after the firststep and after the second step. Any of these VNS delivery methods may beused singularly or in combination.

Other systems may be used to monitor movements, so that appropriate VNStiming can be determined. For a wrist flexion, we might use a camera tomodel the movement as a wire frame (e.g., bones with joints) and comparethe movement to past attempts and to optimal (e.g., normal) movement inorder to find the best movements that the patient can generate.Movements, such as walking, grasping or tying, may be quantified aslocation, direction, speed, and angle of each joint as a function oftime. For speech production, vocalizations might be compared to previoussounds and normal speech sounds produced by others. Vocal movementsmight be quantified based on the intensity, duration, pitch, formantstructure (vowels), formant transitions (consonants), voice-onset time,and other standard methods of quantifying speech sounds.

Selecting the appropriate paired VNS period depends on the nature of themotion and the equipment used to provide the pairing timing.

VNS could also be delivered during the planning stages before movementbegins. This usually takes only a few hundred milliseconds but can beextended by giving a sensory cue that instructs the subject what motionneeds to be done followed by a trigger cue some seconds later tellingthem when to begin the movement. This strategy makes it possible tospecifically pair VNS with motor planning, which is an important part ofmotor control.

VNS may be paired with the best movements in order to shape futuremovements to be smooth and efficient (e.g., avoid spasticity, tremors,co-contraction of opposing muscles, or the use of muscles that would notnormally be used to accomplish the task). VNS could also be deliveredafter the movement is completed and determined to be effective (e.g.,the best movement of the attempts occurring in the last about 30seconds).

Thus, VNS could be delivered before, during, or after movement. Ameasurement may show that the movement will be, is, or was effective(e.g., acceptable or better than average). Pairing may mean temporallyassociated with, not necessarily simultaneous. For the rat studydiscussed below, all VNS was delivered after the end of the targetmovement. However, in many cases, the rats continue with the movementafter the target movement is achieved such that VNS is sometimedelivered while the rat is moving.

VNS may be paired with supervised, massed practice movement therapythree times per week. The duration of the therapy may be six weeks. Theduration of each therapy session may be approximately one hour. Thetherapist may determine each session's therapy tasks to progress towardthe Canadian Occupational Performance Measure (COPM) goals establishedat the intake evaluation. Goals may focus on upper limbrehabilitation—most tasks may typically require four movementcomponents: reaching, grasping, manipulating, and releasing an object.During each session the ‘primary therapy principles’ may be used toguide the development of the tasks to be performed each day. Prior toeach therapy visit, the therapist team may meet and develop the taskplan, ensure available materials and determine the plan to increase anddecrease difficulty to and determine a realistic number of repetitionsto be set as a goal.

The therapy implements several principles. The first principle is taskspecificity. Improvement of a motor skill requires practice of themovement; thus, each task may include components of reach, grasp,manipulate, and release specifically related to the target task.

Another therapy principle is that of repetition. Large numbers ofrepetitions of each task is required to master a motor skill, so thegoal for therapy is to perform from about 30 to about 50 repetitions ofa given task in a one-hour session (about 120-about 200 totalrepetitions per session). The focus of each therapy session may involvefrom about 3 to about 5 tasks in order to achieve the high numbers ofrepetitions.

Another therapy principle is active engagement. Optimal learning occurswith high levels of motivation and engagement. Thus, participants mayhelp to set goals, therapists may make it clear how the target taskrelates to each goal, task practice may be varied to minimize boredom,and the task may be constantly adapted to require active engagement andeffort to complete.

Another therapy principle is massed practice. Within a session, massedpractice promotes better learning than distributed practice. Thus, thetherapeutic environment needs to allow continuous repetition. Forexample, therapist may line up 10 objects in a row to allow forcontinued repetition. Rest breaks are given only if requested by thepatient or required by the VNS.

Another therapy principle is variable practice. Variable practice can beimportant for learning transfer. The movement components may stay thesame, and the context of the components may change between trials orsessions.

The therapy session should consist of from about 3 to about 5 tasks toallow variability and patient engagement. A reach & grasp task may beincluded in each session. The majority of patients need work in thisarea, so including it as a required task allows for consistency betweenpatients and useful in judging rehabilitation with assessments.

The therapy session may, at least initially, take place under thesupervision of one or more therapists. The patient may perform theaction without assistance from the therapist. The therapist may manuallydeliver the VNS trigger during the “key” part of the movement that isbeing trained (typically when the subject touches or is about to touchthe object during the reach). Alternatively, automatic delivery could beused. Tasks may be appropriately graded to require processing and effortby the patient but some degree of success. As a general guideline, ifthe patient is unable to complete the task successfully afterapproximately five attempts, it should be downgraded in difficulty. Thisguideline may be superseded by the therapist's clinical judgmentregarding the patient's motivation, ability, and fatigue. If the patientis able to complete the task with little difficulty approximately (e.g.,from about 10 to about 20 times) it should be upgraded in difficulty. Ifthey can complete it, but it is slower than normal, then it is still achallenging task, and variety may need to be introduced to alleviateboredom.

The upgrading and downgrading of tasks is dependent on the patient'sgoals as well as the effort required. The level of strength andendurance required for the goal is also an important consideration. Forsome patients, even higher repetitions may be required to achieve theendurance needs. The goal for repetitions of each task may be set aheadof time by the therapist and communicated to the patient.

Grading of tasks can involve several different components: Physicalposition of the patient. The patient may be standing to introducevariety, add endurance, and add balance components to the taskperformance. Alternatively, the patient may be sitting.

The position of the task materials may be changed. The height of thetask materials may be changed. The depth of the task materials, placingthe materials further away from patient, may be changed. The degree frommidline of objects (left, midline, or right) may be varied. The weightof task materials may be changed. The size of the objects may bechanged.

Adaptive equipment/materials may be used. A DYCEM mat may be used toprevent an item from sliding. The therapist may hold item to stabilizeit. Materials may be used to increase the grip of a small object tomatch ability (e.g., use foam to build up a pen to make it easier tograsp).

The speed of task movement may be changed. A certain number ofrepetitions per minute may be implemented to focus on the speed ofmovement. The patient may be encouraged to slow down task performance

The stability of the object may be changed. The object to grasp may bestable. The object to grasp may be moving (e.g., a ball is rolling on atable). The object may be placed on slippery surface or a stickysurface.

The same task can be practiced with different forms of material toachieve variety but still maintain high levels of repetition of theoverall task. For example, to work on grasp and release of smallobjects, a plethora of everyday objects could be used, such as coins,paperclips, credit cards, cell phones, etc.

Task performance may be monitored by the therapist, and each VNSstimulation may be recorded by the software and presented to thetherapist as a visual counter on the screen.

If in the therapist's assessment there are other rehabilitation issuesthat may require intervention, such as restricted range of motion, thiscan be addressed outside of the about one hour motor practice oraddressed prior to the start of the VNS therapy. If there aresignificant non-motor impairments, such may disqualify the participant.

Patients may not be given a home exercise program of specific items topractice. However, they may be told to participate in their normal everyday activities and be encouraged to “practice using your impaired upperextremity as much as possible”.

EXAMPLES OF GOAL AND TASK GRADING Example 1 Grasp and Release

The patient's goal is to be able to unload dishwasher. The target taskinvolves the ability to grasp, manipulate, and release a variety ofobjects along with a variety of strength and range of motionrequirements and some degree of endurance (e.g., being able to stand forthe entire duration).

Materials: spoon, fork, knife, large serving spoon, large and mediummixing bowl, coffee mug, drinking glass, small plate, large dinnerplate, a DYCEM mat, foam.

Method: First, Patient sits at table with objects at midline Second, foreach task repetition, the patient reaches out to grasp object and placeon shelf about six feet above the table. Third, 10 objects are lined upto allow continuous repetition of the movement and achieve high numbers.

Grading: The task can be upgraded in difficulty by: challenging patientthat a certain number of repetitions be completed in one minute; using avariety of sizes instead of the same size/shape in a row; requiring thepatient stand to perform; requiring the patient bend down to retrievethe object; requiring the patient reach higher to place the object;requiring the patient sort and place each object in the correct positionin a drawer; mixing bilateral lifting with single hand tasks; silverwareis placed in a basket to be removed from; weight baring is required inone limb to stabilize during a task (e.g., the patient leans on his lessaffected arm and practices wiping the table with the impaired arm);and/or including bilateral tasks that aren't symmetrical (e.g., thepatient uses a spray bottle with the impaired hand and cleans with theless affected arm).

The tasks can be downgraded in difficulty by: wrapping the object infoam to make it easier to grasp; placing objects on a DYCEM mat tominimize slipping; requiring object be moved from impaired hemifield toless impaired hemifield; and/or performing bilateral tasks.

Introducing variety and still achieving high numbers of repetitions.First, the goal for this task is 200+ repetitions. Since the goal is acomplex task that involves several components this may be the only taskperformed is this session. Second, for the first part of the session,the task may be designed to primarily challenge the grasp. Theindividual may grasp objects in a variety of challenging ways with lesschallenge focused on the reach or manipulate aspect of the entire task,for 100 repetitions (e.g., 10 objects×10 repetitions) This may takeabout 25 minutes. There is a line of objects set up, thus there may bevery little rest between repetitions. The second part may have greateremphasis on the reach part of the task, but the task is still repeatingthe components. The individual may now pick up a relatively easy object,that is further away from him, requiring a reach to different aspects ofthe field in front of him. Each of these trials may take longer. He mayperform 35 trials of this from a variety of reach locations, which mayrequire approximately 15 minutes. For variety, the object could be closeand the he would be required to reach at the limits of his ability forthe release of the object. Finally, the third part may focus onmanipulation and precision. For these trials, the initial grasp andreach is not as difficult, but the manipulation/release may be repeated,e.g. about 75 times in about 20 minutes. This may require preciseplacement of an object (e.g., the participant has to stack a set ofspoons on top of each other or place cups in a precise stack. The day'ssession was focused on the goal with all repetitions were focusedspecifically toward the same task, but different aspects of the goalwere emphasized to eliminate boredom and fatigue.

Example 2 Handwriting

The patient's goal involves being able to write checks and thank younotes.

Materials: pen, paper, pencil, dry erase board, cylindrical foam, sandtray, shaving cream, and tray.

Method: First, the patient sits at a table with a tray with a mound ofshaving cream. Second, the patient practices spreading the cream evenlythroughout the tray. Third, the patient practices free writing with afinger or with a stylus. Fourth, the patient practices loop drawing orfree writing with writing utensil of choice. Fifth, the patientpractices filling out forms or line writing within constrained box.

Grading: The tasks can be upgraded in difficulty by: increasing thenumber of words written (e.g., phone number, address, sentences);decreasing task difficulty by using built up writing utensils to aid ingrip; and/or decreasing task difficulty by using dry erase board,shaving cream, writing large letters or loops.

Example 3 Bilateral Activity

The patient's goal involves folding laundry.

Materials: 10 wash cloths, 10 hand towels, 10 bath towels, 10 t-shirts,10 pairs of socks.

Method: First, the patient may sit or stand at the table. Second, thepatient may fold towels at midline. Third, all towels may be folded inhalf and then in half again using bilateral upper extremities. Fourth,folded towels may be placed in laundry basket.

Grading: Tasks may be decreased or increased in difficulty by changingthe size and weight of objects. Tasks may be decreased or increased indifficulty by changing the number of folds required in the object. Taskcan be increased or decreased in difficulty by changing the location ofwhere the object is to be grasped or placed. The therapist may unfoldthe towels to allow rapid repeat of task.

Example 4 Fine Motor Tasks

The patient's goal involves fishing.

Materials: 10 fishing lures, various sized bobbers, fishing weights,fishing line, a tackle box, and a fishing reel.

Method: First, The tackle box is placed at the patient's midline.Second, fishing weights bombers and lures are placed on the affectedside. Third, the patient is instructed to pick up items and place themin the top box. Fourth, the patient is instructed to pick up items oneat a time. Fifth, the patient practice is tying a fishing line. Sixth,the patient practices stabilizing the fishing rod with one hand andreeling with the other hand.

Grading: Increase or decrease task difficulty by increasing ordecreasing the size of the items in the tackle box. Increase or decreasethe difficulty by increasing or decreasing the weight of items at theend of the fishing line.

Example 5 A Discrete, Specific Task

The patient's goal involves opening doors.

Materials: A set of experimental doors knobs with various types oflocks, keys, and actual doors.

Method: First, the key is built up with foam or putty to allow easiergrasp of the key. Second, the knobs/locks are placed at an easilyaccessible height to allow the patient to sit and perform the task.Third, actual doors are used and the patient has to fully open the doorand walk through.

Grading: A variety of knob types are used requiring different aspects ofgrasp. The knobs/locks are placed at progressively more difficultpositions. The actual doors are light or heavy.

Systems and Devices

With reference to FIG. 5, an implantable vagus nerve stimulation system500 is shown in situ. The implantable vagus nerve stimulation system 500includes an IPG 506, electrodes 502, and a lead 504 connecting the IPG506 to the electrodes 502. The IPG 506 may be implanted in the chest ofa patient 512. The lead 504 travels below the skin to the neck of thepatient 512. The electrodes 502 may be of the cuff-electrode type andmay be attached to the left vagus nerve 508 in the neck of the patient512. The IPG 506 sends electrical stimulation pulses through the lead504 to the electrodes 502, causing stimulation of the vagus nerve 508.The IPG 506, lead 504, and electrodes 502 function similarly to theimplantable vagus nerve stimulation systems commonly used in thetreatment of epilepsy and as described in the parent patent applicationto this application.

Vagus nerve stimulation may be delivered with electrodes placed indirect contact (or proximate to) the left cervical vagus nerve, in thepatient's neck. Other forms of stimulation may be used, includingtranscutaneous electrical or magnetic stimulation, physical stimulation,or any other form of stimulation. An example of a transcutaneouselectrical stimulation system that could be adapted for use in thedescribed therapy may be found in U.S. Pat. No. 7,797,042. Stimulationof the vagus nerve may be done at other sites along the vagus nerve andbranches of the vagus nerve.

With reference to FIG. 6, a stroke therapy system 600 is shown. Theimplanted stimulation system 500 communicates wirelessly with anexternal communication device 602. The external communication device iscoupled to a clinical controller 604. The clinical controller 604 may bea computer, such as a laptop computer, running specialized paired VNSstroke therapy software. A manual input device 606 may be coupled to theclinical controller 604. The manual input device 606 may be a handswitch, a foot switch, a mouse button, or a keyboard key. When themanual input device 606 is switched or pressed, the clinical controller604 sends a signal to the external communication device 602. Theexternal communication device 602 sends a signal to the implantedstimulation system 500. The implanted stimulation system 500 receivesthe signal at the IPG 506 and generates stimulation of the vagus nerveat the electrodes 502.

With reference to FIG. 7, a stroke therapy system 700 is shown. Theimplanted stimulation system 500 communicates wirelessly with anexternal communication device 602. The external communication device iscoupled to the clinical controller 604, which may be coupled to manualinput device 606. A camera 608 and sensor 610 may also be coupled to theclinical controller 604. The camera 608 and/or sensor 610 detect motionor attributes of the motion. The data detected by the camera 608 and/orsensor 610 are processed by the clinical controller 604. When the dataindicates a threshold has been reached during the performance of thetherapeutic task, the clinical controller 604 may send a signal to theexternal communication device 602, and the external communication device602 may send a signal to the implanted stimulation system 500. Theimplanted stimulation system 500 receives the signal at the IPG andgenerates stimulation of the vagus nerve at the electrodes. The manualinput device 606 may be used to control the delay between stimulations.

The system may also implement magnet mode, where a hand-held magnet maybe swiped over the IPG in order to cause a stimulation. The specializedstroke software may include a magnet mode setting, to provide for use ofthis mode. When in magnet mode, swiping the hand-held magnet willdeliver a pre-programmed stimulation (i.e. at whatever settings wereprogrammed). The reason for this feature is the physician and patient donot need to be in proximity of the computer/external controller, anarrangement that may work better for some kinds of tasks. When not inmagnet mode the magnet causes stimulation to stop, as a safety feature.

The clinical controller 604 may run specialized stroke therapy software.The specialized stroke therapy software manages patient data, controlsthe stimulations, sets the stimulation parameters, and records data fromthe therapy. FIGS. 8-13 show screenshots from an embodiment of thestroke therapy software. With reference to FIG. 8, a screen shot showsan initial page of the specialized stroke therapy software. The initialpage allows the user to navigate to input screens for programming theimplant, set the therapy parameters, and access patient data. Withreference to FIG. 9, a screen shot depicts the input screen forprogramming the implantable system. With reference to FIG. 10, a screenshot depicts an input screen for further programming the implantablesystem. With reference to FIG. 11, a screen shot depicts an input screenfor advanced settings. With reference to FIG. 12, a screen shot depictsan input screen for implantable parameters. With reference to FIG. 13, ascreen shot depicts a therapy delivery screen. On the therapy deliveryscreen, a therapeutic task may be selected.

With reference to FIG. 14, an automated stimulation pairing system 800is shown. One or more objects 802 such as a cylinder, a key, a block, orany other object suitable for manipulation-type tasks is placed in aworkspace. Portions of the patient's body, such as a hand or fingers,may also serve as objects. The object 802 is marked with a coloredmarker 804 such as a piece of colored tape, a spot of paint, a coloredsticker or any appropriate manner of marking an object with color. Forsome tasks, such as rotation, the colored marker 804 needs a long edgeand a short edge, as shown. Any object 802 can be marked with a stickeror tracking sphere and tracked for the therapy. A camera 608 or aplurality of cameras 608 are placed around the workspace so that theobject 802 and the marker 804 is within view of the camera 608. Cameras608 may also be used to monitor the patient rather than an object ormarker. In accordance with an embodiment, a camera may be placed abovethe workspace. The cameras 608 are connected to the clinical controller604. Specialized software running on the clinical controller 604 usesdata from the cameras 608 to determine the relative position, velocity,rotation or any other metric related to the performance of the giventask. The clinical controller 604 uses the determined metric to decidewhen stimulation is appropriate and sends a stimulation signal to theexternal communication device 602. A manual interrupt 606 may beimplemented so that a therapist can interrupt and control the rate ofstimulation. The automated system 800 may be completely automated, in aclosed loop setup so that the next stimulation is automatic. Theautomated system 800 may be arranged in an open loop fashion, so thatthe therapist must intercede before the next stimulation.

The specialized software monitors x,y,z translations of objects with anattached target. The specialized software includes parameters for avariety of tasks that may be performed using this type of closed loopautomated system. Using a single camera and colored markers, a widevariety of tasks can be automated. Motion, speed, height, initiation oftranslation, acceleration, angular rotation, angular velocity, angularacceleration, force, velocity, acceleration, angular acceleration, pathlength, time to target, distance traveled to target, range of motion,height of object and combinations of these and other metrics can be usedto trigger stimulation. Some example tasks include: slide a cup, lift acup, spin a cup, Lift a cup and move it to some other location, move anobject by rotating your wrist, turn a key, flip a coin, pick up a spoon.Tasks may be combinations of movements or tasks, such as lifting a cupand bring it to the mouth, lifting a penny and putting it on a shelf,lifting a key, putting it in a lock and turning the key, or sliding acup to some point, picking it up, and spinning it 30 degrees. The tasksmay be designed to isolate movements of specific muscle groups. Adaptivetracking of a base metric, based on past performance within a session orbetween sessions, can be used to generate improvement.

The automated paired stimulation system may be arranged so that when theobject 802 is moved into or out of a pre-defined boundary that surroundsthe object, vagus nerve stimulation is triggered.

A marker 804 can be placed on the patient's hand or arm rather than onan object.

When the object 802 when lifted or lowered in the z-axes i.e. towardsthe camera 608, the change in the area of the marker 804 may be detectedand used to trigger stimulation.

The object 802 may be moved to specified places on the surface. Forexample, the task may require the patient to move the task object 802 toa square on the surface. When the object is successfully moved to thesquare, the VNS stimulation is triggered.

Stimulation is triggered during the movements. The specialized softwaremay stimulate on the best trials, such as shortest path length, fastestmovement, optimal acceleration, minimal jitter, maximum height and othermetrics, to provide pairing with improved performance.

The manual interrupt 606 may be adapted to require the therapist after astimulation from the automatic software to press the manual interrupt606 to indicate a new stimulation can be permitted. This allows thephysician or patient to reset the object 802 or for the physician todemonstrate the movement without accidentally causing a stimulation.

In accordance with another embodiment, EMG (muscle electrical activity)may be measured and used to trigger paired vagus nerve stimulation. Itis also possible to quantify or image specific movements of the patientsuch as a patient's walking gait, eye position or tongue position andpair them with VNS. Muscle activity in muscle groups that are onlypartly under voluntary control (e.g. bladder and sphincter) may be usedto trigger paired vagus nerve stimulation.

The automated system may support such tasks as: Reach and grasp; Reachand grasp (small/large objects) (gross and fine movements, dexterity);Point and/or press objects with finger (accuracy); Insert small objectsinto wells of different sizes (accuracy); Flip cards or sheets of paper(Circumduction and dexterity); Lift objects from table; Circumductionand bimanual tasks (mainly involving wrist and distal joints); Lock andkey (Circumduction); Turning a doorknob (Circumduction); Open and closea pill bottle (bimanual; flexion extension wrist); Pour water from apitcher to glass (bimanual).

Motion can be detected using a camera or other detection devices. Thesystem may operate by detecting change in color of the object by acamera, breaking an IR beam PIR motion sensor, engaging a forcetransducer, turning a knob or dial potentiometer, pressing a button,flipping a switch, activating a motion sensor, activating apiezoelectric sensor, ultrasonic sensors for detecting distance, or anyother appropriate measure of motion.

The automated system may be designed to do is to determine a “good”trial and only stimulate on a good trial. A good trial may be determinedby comparing the history of past movements, running an appropriatealgorithm on a clinically relevant parameter(s) and using thisdetermination to trigger stimulation. Good could be defined ahead oftime by speed, acceleration, strength, range of motion, like degree ofwrist turn, or any other appropriate defining quality.

Similar automated systems are described in U.S. Pat. Nos. 6,155,971 and7,024,398.

With reference to FIG. 15, a screenshot of a specialized automatedpairing software is depicted. Patient data and motion parameters may beentered or selected. A camera view detects the motion of an object andprovides vagus nerve stimulation, in accordance with the selectedparameters.

Support

Although sensory and motor systems support different functions, bothsystems can exhibit topographic reorganization of the cortex followingtraining or injury. Tone training (conditioning or artificialstimulation) can increase the representation of the tone in the auditorycortex. Operant training on a tactile discrimination task increasedsomatosensory cortical representation of the digit used in training.Similar changes can occur in the motor cortex following training withprecise digit movements. Motivation and frequency of training influencethe degree of cortical map plasticity. Deprivation caused by peripheralinjury changes the organization of sensory and motor cortices. Forexample, digit amputation or nerve transection causes receptive fieldsin the inactivated somatosensory cortex to shift to neighboring digits.Likewise, transecting the facial nerve reduces the number of motorcortex neurons that elicit vibrissae movements while increasing thenumber eliciting forelimb movements. Targeted lesions to the sensory ormotor cortex can cause the surrounding healthy cortical areas to take onsome of the damaged area's lost functionality. Drugs that blockreorganization of cortical representations in the sensory cortex canalso block reorganization in the motor cortex. Collectively, theseresults suggest that the mechanisms regulating cortical plasticity arecommon to both sensory and motor cortices.

The vagus nerve may send afferents to a number of nuclei known torelease neuromodulators associated with cortical plasticity, includingthe locus coreleus, raphe nuclei, and the basal forebrain. The vagusnerve has several efferents to major organs in the body, including theheart; however, a large portion of the vagus nerve consists of afferentconnections to several targets in the midbrain. Low-current stimulationof the left vagus nerve is a commonly used treatment for drug-resistantepilepsy that is associated with minimal risks. Complications associatedwith stimulation to the heart are avoided due to the limitedcontributions of the left vagus nerve to cardiac activity and theminimal levels of current. Unilateral stimulation of the vagus nerve canresult in bilateral activation of the nucleus of the solitary tract andits projections to the locus coeruleus and raphe nucleus. Activation ofthe locus coeruleus can lead to activation of the nucleus basalisthrough al adrenoreceptors. Although the exact mechanisms of action arenot entirely yet understood, VNS has demonstrated several beneficialeffects for major depression, mood enhancement, improved memory,decision making, and improved cognitive abilities in Alzheimer'spatients, and it reduces edema following brain trauma. Due to the knownrelease of multiple neuromodulators, VNS has recently become an objectof study in regulating cortical plasticity.

Pairing VNS with motor therapies can be accomplished using several typesof pairing systems. A timing control device can initiate or provide thetherapy and the VNS at appropriate times. A timing control device canmonitor the therapy and provide VNS at appropriate times during thetherapy. A timing control device can receive manual inputs from apatient or clinician during the therapy and generate VNS at appropriatetimes.

Several experiments have been performed that demonstrate theeffectiveness of pairing motor therapy with VNS. The methods and resultsof those experiments are described below.

The wheel spin task required the rat to spin a textured wheel towardsthemselves. Rats used movements of the wrist and digits to complete thistask. Stimulation and reward occurred after the rat spun the wheel about145° within about one second period. The lever press task required therat to depress a spring-loaded lever twice within about 0.5 seconds. Therange of motion required to complete this task pivoted primarily aroundthe shoulder joint. Stimulation and reward occurred after the secondlever press.

Although sensory and motor systems support different functions, bothsystems exhibit dependent cortical plasticity under similar conditions.If mechanisms regulating cortical plasticity are common to sensory andmotor cortices, then methods generating plasticity in sensory cortexshould be effective in motor cortex. Repeatedly pairing a tone with abrief period of VNS increases the proportion of primary auditory cortexresponding to the paired tone. It was predicted that repeatedly pairingVNS with a specific movement would result in an increased representationof that movement in primary motor cortex. As such, VNS was paired withmovements of the distal or proximate forelimb in two groups of rats.After about five days of VNS movement pairing, intracranialmicrostimulation was used to quantify the organization of primary motorcortex. Larger cortical areas were associated with movements paired withVNS. Rats receiving identical motor training without VNS pairing did notexhibit motor cortex map plasticity. These results suggest that pairingVNS with specific events may act as a general method for increasingcortical representations of those events. VNS-movement pairing couldprovide a new approach for treating disorders associated with abnormalmovement representations.

Repeatedly pairing VNS with a tone may cause a greater representation ofthat tone in primary auditory cortex. This map expansion is specific totones presented within a few hundred milliseconds of VNS. No previousstudy has reported the effects of pairing VNS with a specific movementon cortical plasticity. If the mechanisms regulating map plasticity inthe auditory cortex are the same in the motor cortex, then VNS-pairedwith a movement should generate map plasticity specific to the pairedmovement. In one embodiment, VNS was paired with a specific movement totest if this method could be used to direct specific and long-lastingplasticity in the motor cortex.

In one embodiment, thirty-three rats were randomly assigned to receive avagus nerve cuff electrode or a non-functional, sham vagus nerve cuffelectrode. After recovery from the surgery implanting the nerve cuff,thirty-one rats were trained to perform one of two operant motor tasksusing either their proximal or distal forelimb. After the rats learnedto reliably generate the required movement, VNS was paired with themovement several hundred times each day for about five days. Fortwenty-five of these rats, intracranial microstimulation (ICMS) was usedto quantify the reorganization in the primary motor cortex about 24hours after the last training session. Instead of ICMS, six of thenon-stimulated rats received ischemic motor cortex damage and wereretested to confirm that accurate performance of the task requires motorcortex. Motor cortex ICMS was performed on two rats that had functionalVNS electrodes and received the same amount of VNS but received no motortraining Δn additional group of eight experimentally naïve rats that hadnot received motor training or VNS also underwent motor cortex ICMS.

A comparison of the motor maps from the rats with sham cuffs to the ratswith functional cuffs allows a determination as to whether pairing VNSwith the movements enhances cortical plasticity. Comparison of the motormaps from rats that were performing a task during VNS with rats thatwere not performing a task during VNS allows a determination as towhether the motor task was required to generate motor cortex plasticity.

Forty-one adult, female Sprague-Dawley rats were used in thisexperiment. The rats were housed in a 12:12 hour reversed light cycleenvironment to increase their daytime activity levels. During training,the rats' weights were maintained at or above 85% of their normal bodyweight by restricting food access to that which they could obtain duringtraining sessions and supplementing with rat chow afterward whennecessary.

Rats were implanted with a custom-built cuff electrode prior totraining. Stimulating cuff electrodes were constructed as previouslydescribed. In one embodiment, two TEFLON-coated multi-stranded platinumiridium wires were coupled to a section of Micro-Renethane tubing. Thewires were spaced about two mm apart along the length of the tubing. Aregion of the wires lining the inside circumference of the tube abouteight mm long was stripped of the insulation. A cut was made lengthwisealong the tubing to allow the cuff to be wrapped around the nerve andthen closed with silk threads. This configuration resulted in theexposed wires being wrapped around the vagus nerve at points separatedby about two mm, while the leads exiting the cuff remained insulated.These insulated wires were tunneled subcutaneously to the top of theskull and attached to an external connector. A second group of randomlychosen rats received similar cuffs, but with silk threads in place ofthe platinum iridium wires.

In one embodiment, all the steps of the surgeries were the sameregardless of the type of cuff implanted. Rats were anesthetized usingketamine hydrochloride and xylazine with supplemental doses provided asneeded. After rats were no longer responsive to toe pinch, incisionsites atop the head and along the left side of the neck were shaved andcleaned with betadine and about 70% isopropyl alcohol. The applicationof opthomalic ointment to the eyes prevented corneal drying during theprocedure and a heating pad maintained the rats' body temperature atabout 37° Celsius (C). Doses of cefotaxime sodium and adextrose/Ringer's solution were given to the rats before and during thesurgery to prevent infection and provide nourishment throughout thesurgery and recovery. Bupivicaine injected into the scalp and neckfurther ensured that the rats felt no discomfort during surgicalprocedures. An initial incision and blunt dissection of the scalpexposed the lambda landmark on the skull. Four to five bone screws weremanually drilled into the skull at points close to the lambdoid sutureand over the cerebellum. After an acrylic mount holding a two-channelconnector was attached to the anchor screws, an incision and bluntdissection of the muscles in the neck exposed the left cervical branchof the vagus nerve. As in humans, only the left vagus nerve wasstimulated because the right vagus nerve contains efferents thatstimulate the sinoatrial node and can cause cardiac complication.

In one embodiment, eighteen rats received the platinum iridium bipolarcuff-electrodes while another thirteen received the sham cuffs in whichsilk thread replaced the platinum iridium wires. Leads (or silk threads)were tunneled subcutaneously and attached to the two-channel connectoratop the skull. All incisions were sutured and the exposed two-channelconnector encapsulated in acrylic. A topical antibiotic cream wasapplied to both incision sites. After surgery, the rats with silkenthreads looked identical to the rats with wired cuffs after thesurgeries. Rats were provided with amoxicillin (about 5 mg) andcarprofen (about one mg) in tablet form for three days following thesurgeries and were given one week of recovery before training began.During the week of recovery, rats were habituated to having thestimulator cable coupled to the two-channel connector on their heads.This method of cuff electrode construction, implantation, andstimulation delivery has repeatedly been shown to consistently result inVNS that persists over the full-term of the experiment.

In one experiment, rats were trained on either the wheel spin task (n=10rats) or the lever press task (n=21 rats). Training occurred in twodaily sessions for five days each week. Both tasks involved quickmovement of the forelimb in order to receive a sugar pellet reward. Ratsinitiated each trial, but a delay of at least two seconds was requiredbetween trials to allow the rats to eat the sugar pellet. The wheel spintask required the use of muscles located primarily in the distalforelimb, especially the wrist, while the lever press task required theuse of the shoulder and the proximal forelimb.

The initial shaping procedures were similar for both motor tasks. In oneembodiment, rats were placed in a cage and allowed to freely explore thearea. A tether was coupled to the rats' heads to familiarize the animalswith the feeling of the connection. Each time the rats approached theresponse device (e.g., the lever or wheel), they received a 45 mg sugarpellet dispensed into a pellet dish located within the cage.Restrictions were gradually placed on rewarding the rats' proximity tothe response device until the rats had to be next to, and then touching,and finally using the device to receive the reward. An experimenterconducted shaping procedures manually. Rats typically took four30-minute sessions to become familiarized to the response device. Aftershaping, all training sessions were automated using custom-writtenprograms.

In one embodiment, rats that trained on the wheel spin task wererequired to spin a textured wheel below the floor of the training cageto receive a sugar pellet reward. Trials were initiated by the rats, butrewards were spaced at least two seconds apart by the computer program.In one embodiment, rats were initially rewarded for spinning the wheelabout 3° within a one-second period when each new stage began. Afterabout 35 successful spins of the wheel, the degree of rotation requiredfor a reward increased to about 30°, then about 75°, and finally about145°. After about 35 rewards at the highest rotational requirement, therats advanced to the next stage of training (e.g., more restrictedaccess to the wheel) where they repeated all of the levels of increasingrotation again as previously described. Rats demonstrated a pawpreference early in training and continued to use that paw for theremainder of the sessions.

In one embodiment, rats depressed a lever initially located inside thetraining cage to receive a sugar pellet reward. The training cage was awire cage with dimensions of approximately 20 centimeter (cm)×20 cm×20cm with a Plexiglas wall opposite the door. In one embodiment, alltraining sessions other than the shaping sessions were about fifteenminutes long and occurred about twice daily. Trials were initiated bythe rats, but rewards were only given to trials occurring at least fiveseconds apart. After receiving about 60 pellets in about two shapingsessions by pressing the lever, the rats learned to press the levertwice in an about three-second period for the same reward. The intervalbetween lever presses that elicited a reward was reduced from aboutthree seconds to about two seconds, then about one second, and finallyabout 500 milliseconds (ms), with about 15 successful trials as thecriterion for advancing. After successfully pressing the lever twicewithin about 500 ms about forty-five times, the lever was graduallywithdrawn out of the cage. The lever was initially located about four cminside the cage, then moved to about two cm inside the cage, and then toabout 0.5 cm, about 1.5 cm, and about 2.0 cm outside of the cage. Thecriterion for retracting the lever was about 15 successful double-leverpresses for each position, except for about 0.5 cm outside the cage,which required 30 successful trials. In one embodiment, rats reachedthrough a window in the Plexiglas wall that was about one cm×about sevencm to reach the lever outside the cage. The edge of the window waslocated about two cm from the cage wall, while the lever was offset sothat the middle of the lever lined up with the edge of the windowfurthest from the wall. This arrangement restricted the rats so thatthey could only comfortably press the lever with their right paw. Thisaspect of the task design was important for confirming the importance ofthe motor cortex for the lever press task with motor cortex lesions.

To confirm that accurate performance on the lever press task requiresmotor cortex, six rats implanted with the nerve cuffs and trained on thelever-press task without stimulation received motor cortex lesions andwere retested for about two days following about one week of recovery.Based on procedures by Fang et al., (2010), the vasoconstrictorendothelin-1 was used to selectively lesion the caudal forelimb area ofthe motor cortex. Basic surgical procedures for cleaning, anesthesia,and post-surgical care were the same as the cuff implantation surgery.After cleaning the top of the head, an incision was made longitudinallyand a craniotomy was performed over the primary motor cortex caudalforelimb area contralateral to the trained forelimb (about 2.75 mm toabout −0.75 mm anteroposterior and about 2.25 mm to about 3.75 mmmediolateral, relative to bregma). Endothelin-1 (about 0.33 microliters(μL) of about 0.3 micrograms (μg) mixed in about 0.1 μL saline) wasinjected at a depth of about 1.8 mm using a tapered Hamilton syringealong a grid within the craniotomy at about 2.5 mm, about 1.5 mm, about0.5 mm, and about −0.5 mm anteroposteriorally, and about 2.5 mm andabout 3.5 mm mediolaterally relative to bregma for a total of eightsites according to one embodiment. KwikCast silicone gel was used toreplace the removed skullcap and the skin was sutured. The lever presstask was the only task tested with motor cortex lesions due to the easewith which the forelimb used in the task could be restricted. The leverpress task could not be completed with the left forelimb because of thecage design. Lesions were made in the left motor cortex forcing the ratto try to use its impaired right forelimb to complete the task.Impairments to the distal forelimb accompany impairments to the proximalfollowing motor system lesions. Additionally, the lesion size covers theentire caudal forelimb area; therefore, it is expected that impairmentsto the lever press task would also indicate impairments to the wheelspin task.

During the final stage of the motor tasks, reaching through a windowabout 1.2 cm wide and spinning the wheel about 145° within about onesecond period or pressing the lever located about two cm outside thecage twice within about 500 ms triggered a food reward and VNS.Stimulations were delivered approximately 75 ms after the wheel reached145° or the lever triggered the second press. Rats typically continuedto spin the wheel or press the lever beyond the required criterion, suchthat the movements were still occurring during VNS. In one embodiment,VNS was always delivered as a train of about 15 pulses at about 30 hertz(Hz). Each about 0.8 milliamps (mA) biphasic pulse was about 100microseconds (μs) in duration. The train of pulses was about 500 ms induration. Previous studies have demonstrated that the amplitude ofelectroencephalographic measures may be reduced and neuronal desynchronymay increase during VNS using the described electrode implantation,which may indicate a successful stimulation of the vagus nerve.VNS-movement pairing during the final stage of training continued forone week (in one embodiment, 10× about 30 minute sessions for thewheel-spin task and 10× about 15 minute sessions for the lever-presstask), delivering around 1,200 total stimulations. Previous research hasshown that this form of VNS does not alter heart rate, blood oxygenationlevel, or ongoing behavior, suggesting that the stimulation is neitheraversive nor rewarding to the animals.

In one embodiment, connections and stimulations from the externalstimulator to the rats were identical between rats implanted withfunctional or sham VNS electrode cuffs. The sham cuffs with silk threadsin place of platinum iridium leads did not carry an electrical chargewhen stimulated. This difference in the cuffs allows experimenters toremain blind during training to stimulated and sham rats.

The day after the last training session of VNS movement pairing, theorganization of primary motor cortex contralateral to the trained pawwas defined using standard ICMS mapping procedures. In one embodiment,an additional eight rats that did not train or receive VNS alsounderwent ICMS procedures to the left cortex to compare the effects oftraining on motor cortex organization. After placing the rat in astereotaxic frame with a digital readout, a craniotomy was performed toexpose the motor cortex. In one embodiment, parylene-coated tungstenelectrodes were inserted to a depth of about 1,800 micrometers.Stimulation occurred following a grid with about 500 μm spacing.Sequential electrode placements were made at least one mm apart wherepossible. ICMS was delivered once per second. In one embodiment, eachstimulation consisted of an about 40 ms pulse train of about ten 200 μsmonophasic cathodal pulses delivered at about 286 Hz. Stimulationintensity was gradually increased (from about 20 to about 200microamperes (μA)) until a movement was observed. If no movement wasobserved at the maximal stimulation, then the site was deemednonresponsive. The borders of primary motor cortex were defined based onunresponsive sites and stopped at the posterior-lateral vibrissae area,which is known to overlap the somatosensory cortex.

In one embodiment, motor mapping procedures were conducted with twoexperimenters, both blind to the experimental condition of the rat. Thefirst experimenter placed the electrode and recorded the data for eachsite. Because the motor cortex is organized with similar movements oftenoccurring in the general vicinity of each other, the second experimenterwas kept blind to the electrode placement to avoid potential biasing.The second experimenter delivered stimulations while observing whichparts of the body moved in response. Movements were classified based onthe part of the body that moved using the threshold stimulation current.Larger movements were obtained using higher current stimulations andwere used when necessary to disambiguate movements too small toconfidently classify at threshold levels. The first stimulation site wasplaced in an area often resulting in movement of the lower forelimb.Subsequent stimulation sites were randomly chosen and did not extendbeyond established border (e.g., unresponsive) sites. Movements of thevibrissae, face, eye, and neck were classified as “head”. Movements ofthe shoulder, elbow, and upper forelimb, e.g., proximal forelimb, wereclassified as “upper forelimb”. Movements of the wrist and digits werecalled “distal forelimb”. “Hindlimb” included any movement in thehindlimb of the rat. Cortical area was calculated by multiplying thenumber of sites eliciting a response by about 0.25 mm². Four sites equalabout one mm².

To confirm that VNS alone does not produce motor cortex mapreorganization, two rats that were never trained to perform a motor taskwere placed into a training cage and received randomly delivered VNS(e.g., not paired to a specific movement). Except for the movementpairing, VNS in this group was identical to the groups above. In oneembodiment, each animal was passively stimulated for two 30-minutesessions per day with an about two-hour break between sessions, andrepeated for about five days. Within each session, stimulation occurredfor a time from about 8 to about 16 seconds, giving an averagestimulation time of about 11.25 seconds. At the end of each session,about 160 stimulations were given, which amounted to about 1,600stimulations. Animals were ICMS mapped about 24 hours following thefinal passive VNS session.

Rats were shaped to the wheel spin task in about 4±0.3 sessions and thelever press task in about 4±0.3 sessions. Rats reached the last stage ofthe wheel spin task in about 27±5 sessions and the lever press task inabout 8±1 session. The percent of successfully completed trials on thewheel spin task on the first day of VNS paired training was about 77±4%.The same measure for the lever press task on the first day of VNS pairedtraining was about 78±4%. Microelectrode mapping techniques were used todetermine the organization of the motor cortex after five days of VNSpaired training on the last stage. Maps of the motor cortex were derivedfrom about 3,595 electrode penetrations (average about 103 sites peranimal).

In all rats tested, the anterior portion of the motor map generatedmovements of the rat's head, including the jaw, vibrissa, and neck. Themiddle region of the map generated movements of the forelimb and theposterior region generated movements of the hindlimb. As in earlierreports, it was possible to divide the forelimb area into a smallrostral region that is mostly surrounded by head responses and a largercaudal forelimb area that borders the hindlimb area.

In one embodiment, the organization of primary motor cortex was notsignificantly altered by training without VNS. The average arearepresenting the distal forelimb, proximal forelimb, head, and hindlimbwere not significantly different across the naïve, wheel spin, or leverpress trained rats that had sham VNS cuffs electrodes and received noVNS. As a result, these three control groups are averaged for groupanalyses and referred to as the non-VNS group.

In one embodiment, rats that received VNS paired with the wheel spintask exhibited a significant reorganization of the motor cortex. In thenon-VNS rats, the head and distal forelimb occupy approximately the sameamount of cortical area Hindlimb and proximal forelimb comprises asmaller region of the motor map. Wheel spin/VNS pairing resulted in anabout 15% larger distal forelimb area (about 1.0 mm²), an about 25%smaller head area (about −1.75 mm²), and no proximal forelimb area inthis particular animal compared to the naive. These changes in corticalarea for the Wheel spin/VNS paired group were pronounced when comparedto the non-VNS group. On average, pairing VNS with the wheel spin taskresulted in an about 32% increase in the cortical area representing thedistal forelimb compared to the non-VNS group. This increase wasaccompanied by an about 38% smaller head area and an about 63% smallerproximal forelimb area, but no change in the area devoted to hindlimb.These results suggest that repeatedly pairing VNS with a particularmovement can generate a specific increase in the motor cortexrepresentation of that movement.

To confirm that the observed cortical plasticity was specific to themovement paired with VNS, the reorganization of motor cortex wasdocumented in rats that received VNS paired with a lever press task.Since this task primarily involves movement of the proximal forelimb, anincreased proximal forelimb representation after lever press/VNS pairingwas expected. The lever press/VNS rat had about 1600% (about four mm²)more area devoted to the proximal forelimb area compared to the naïverat. Pairing VNS with the lever press movement reduced the head area byabout 39% (about −2.75 mm²) and distal forelimb area by about 59% (about−4 mm²) in this rat compared to the naïve rat. Like the wheel spin/VNStrained rat, the lever press/VNS rat had the same sized hindlimbrepresentation as the naïve rat. These examples suggest that the motorcortex plasticity observed following VNS-movement pairing may bespecific to the paired movement and not a general effect of VNS.

On average, rats that received VNS during the lever task exhibited about159% increase in the proximal forelimb area compared to the non-VNSgroup. The lever press/VNS group had an about 23% smaller distalforelimb area and an about 29% smaller head area than the non-VNS group.The most profound differences were observed between the wheel spin/VNSrats and the lever press/VNS rats. Although both groups receivedidentical VNS, wheel spin trained rats had an about 72% larger distalforelimb area than the lever press rats and the lever press rats had anabout 598% larger proximal forelimb area compared to the wheel spintrained rats. These results may demonstrate that VNS-movement pairingcan generate large-scale reorganization of motor cortex and confirm thatthe reorganization is specific to the movement repeatedly paired withVNS.

In one embodiment, VNS was delivered at random times in two rats beforedocumenting the organization of motor cortex using ICMS techniques.Motor cortex in these rats was similar to naïve rats and there was noevidence of the reorganizations that were observed after either thelever press or the wheel spin movements were paired with VNS. Thisobservation combined with task specificity of the motor cortexplasticity observed in the trained rats that received VNS suggests thatVNS-movement pairing may be sufficient to generate motor cortexreorganization.

In one embodiment, there was no difference in the average stimulationthresholds for the groups receiving movement paired VNS and the non-VNSgroup. The differences in average stimulation thresholds between paststudies and the current study may be due to our using a somewhat deeperlevel of anesthesia. The rats trained with VNS paired on the wheel spintask had an average distal forelimb stimulation threshold not toodifferent from the wheel spin trained group with sham VNS cuffelectrodes. The VNS paired with lever press group's proximal upperforelimb stimulation thresholds was not considerably different from thelever press group trained with sham VNS cuff electrodes. Similarstimulation thresholds between paired-VNS and non-VNS trained ratsdemonstrate that the observed movement representation reorganizationsare not due to altered levels of excitability in the cortex. This resultis consistent with several papers that have found corticalrepresentation changes in the motor cortex from training occurs withoutICMS threshold changes. Morphological changes, such as synaptogenesis,have been observed with past motor cortical reorganization accompanyingtraining and may account for a mechanism of change in movement pairedVNS.

The performance on the lever press task before and after ischemic motorcortex damage in six rats was compared. In one embodiment, performancewas markedly impaired in every rat. Average performance fell from 93±1%successful double-tap attempts for the last two days before surgery to75±5% for the two days of testing conducted after a week of recovery.This result tends to confirm that this task like other skilled motortasks may depend on motor cortex for accurate performance.

The task performance in each group was compared to confirm that movementpaired VNS does not make the task more difficult. In one embodiment, nobehavioral differences were observed between VNS and sham groups on thewheel spin task in the total number of successful trial, the velocity atwhich the wheel was spun, or the percentage of successfully completedtrials per session. VNS rats showed no impairment on the lever presstask and, in fact, exhibited shorter lever press intervals and triplepressed the lever more often than the sham rats. Although VNS enhancedsome aspects of the lever press task, the percent of successful trialsand the total number of successful trials were not different between theVNS and sham rats. These results may indicate that VNS is unlikely tohave enhanced map reorganization by making the task more difficult.

It was predicted that repeatedly pairing brief stimulation of the vagusnerve with a specific movement would result in a larger representationof that movement in the motor cortex. As such, about 0.5 sec of VNS wasdelivered each time rats used their distal forelimb to rotate a wheel.After several hundred pairings, the cortical representation of thedistal forelimb was markedly larger in these rats compared to naïve ratsand rats that performed the same movements without VNS. A second groupof rats was trained on a motor task using a different part of their bodyto confirm that map reorganization was specific to the movement pairedwith VNS. Pairing VNS with a lever press task that required the use ofthe proximal forelimb resulted in a markedly larger proximal. Impairedperformance in a group of rats following ischemic lesions to the caudalforelimb area tends to confirm the involvement of the motor cortex inthis task. The observations that map expansion was specific to themovement paired with VNS and that neither of the tasks without VNS norVNS without the task training generated map reorganization indicatesthat movement paired VNS is sufficient to direct map plasticity.

Pairing VNS with a motor event generated cortical plasticity comparableto that observed using a similar paradigm in the auditory system.Presenting a tone with a brief period of VNS causes a significantexpansion of the paired tone's representation in the auditory cortex.Presenting tones or VNS alone did not alter the auditory cortex'stonotopic organization. These two studies suggest that the plasticityenhancing mechanisms of event-paired VNS may be shared with the auditoryand motor cortex.

A number of studies have reported that training on skilled motor tasksincreases cortical representations for the movements involved. Theresults disclosed herein do not contradict these findings, as one of thelandmark studies demonstrating training induced cortical plasticityusing a skilled reaching task also demonstrated a lack of reorganizationfor a lever press task. The lack of observed cortical change followingtraining on the lever press and wheel spin tasks may be due to a numberof reasons. The cortical reorganization observed in a skilled reachingtask has been attributed to the accuracy of the movements necessary tocomplete the task which may be absent in our lever press and wheel spintasks. There is also a possibility that the sampling distance of about500 μm is too coarse to see cortical changes associated with tasks inthe current study, although this spacing has previously demonstratedtraining induced plasticity in the aforementioned skilled reaching task.Another possibility is the cortical changes observed following motor andauditory learning have been shown to be transient while the acquiredskill remains stable over time. The lever press and wheel spin trainedrats were mapped approximately 10 and 20 days after their initialtraining session, respectively, possibly occurring after corticalchanges associated with training would have been observed. If thispossibility occurred, then the VNS-paired training may have prolonged orreestablished the observed changes in the motor cortex organization.

The exact mechanisms by which VNS directs plasticity in motor or sensorycortex are unknown. VNS causes the release of several molecules known toenhance cortical plasticity, including acetylcholine, norepinephrine,serotonin, and brain derived neurotrophic factor. Perfusingnorepinephrine into an adult cat's visual cortex produces kitten-likeplasticity in a test of ocular dominance shifts following monoculardeprivation. Serotonin specific neurotoxins and receptor blockersprevent normal ocular dominance shifts in kittens in monoculardeprivation, implicating the importance of serotonin for normalplasticity. Another important study showed that enhancing serotoninrelease with fluoxetine can stimulate plasticity in adult cats. Blockingthe release of acetylcholine prevents cortical plasticity and interfereswith skill learning and recovery from brain damage. The use of themuscarinic antagonist scopolamine blocks the effect of VNS onspontaneous firing rate in the auditory cortex, further supporting theinfluence of VNS on the cholinergic system. Adding brain derivedneurotrophic factor induces plastic changes in ocular dominance shiftsin adult rats following monocular deprivation. Combining more than oneof these elements can lead to greater plasticity than the influence ofthe elements singularly. The ability of VNS paired with wheel-spin orlever-press training to produce cortical plasticity supports theimportance of the VNS triggered release of these molecules in enhancingcortical plasticity. VNS is likely to generate cortical map plasticityspecific to the associated event through the synergistic action ofmultiple plasticity enhancing molecules.

The simultaneous presentation of VNS with a specific sensory or motorevent can be sufficient to increase cortical representation of thatmovement. As discussed above, a sugar pellet was used to reward theanimal's behavior immediately after the completion of a trial. As aresult, VNS was delivered during the behavioral task that finished justa few seconds prior to the animal eating the pellets. It would not havebeen surprising to see an increased representation of the head and jawin this study.

In a previous study, our lab demonstrated that changes in auditorycortex were temporally specific to tones paired with VNS. Two randomlyinterleaved tones were presented every about 15 to about 45 seconds forseveral thousand trials to a rat with only one of the tones paired withVNS. The number of sites responding to the VNS paired tone increasedsignificantly, while the number of sites for the tone presented withintens of seconds of the VNS did not. These observations are consistentwith past studies demonstrating that pairing nucleus basalisstimulations with tones only alters the tone's representations whenstimulations occurred within seconds of the tone presentation.

The results disclosed herein demonstrate that the head representationsdid not increase because of VNS just prior to chewing. This resultindicates that the plasticity enhancing actions of VNS are temporallyprecise, lasting less than about one or about two seconds. These resultsdemonstrate that brief pulses of VNS can be used to direct highlyspecific plasticity. Additionally, VNS without paired behavioraltraining did not result in map reorganization, further supporting ourconclusion that the cortical changes triggered by VNS are enhanced bytask specific pairing. Methods for enhancing plasticity that rely onslow-acting mechanisms may not be as effective in generating the sameaccuracy of plasticity as VNS-pairing. Pharmaceuticals often elevate ordiminish certain neurotransmitters for several hours. Several movementsor sensory events may occur repeatedly during this time, potentiallycreating unwanted plasticity. The temporal precision of the VNS-pairingmethod for enhancing cortical plasticity should offer advantages inefficiency and efficacy as compared to methods with less preciseactions.

In one embodiment, motor map expansions did not accompany enhanced taskperformance in rats trained on the VNS paired wheel spin or lever presstasks. This is not necessarily at odds with the prediction that eventpaired VNS increase functional recovery through increasing functionalplasticity following cortical damage. Map reorganization has been shownto be important for enhancing behavioral outcomes during the learningprocess (Reed et al., 2011). Rats demonstrating increased tonotopicrepresentations for low frequencies following paired nucleus basalisstimulation demonstrated faster learning of a tone discrimination taskcompared to controls. However, rats that had already learned the tonediscrimination did not behaviorally benefit from the induced plasticity.From these results, the authors concluded that “cortical map expansionplays a major role in perceptual learning but is not required tomaintain perceptual improvements”. In the present disclosure, the ratshad already learned the tasks when they began receiving VNS, otherwisethey may have demonstrated an accelerated learning rate compared to thesham groups. The enhanced propensity for cortical reorganizationaccompanying event-paired VNS may increase rehabilitative learning.

Stroke and traumatic brain injury often damage movement-controllingareas of the motor cortex resulting in hemiparesis or hemiplegia.Following cortical injury, lost motor representations can partiallyregenerate in neighboring areas within motor cortex. The size of theregenerated representations is highly correlated with the functionalrecovery of lost movements, but this recovered area and ability is afraction of those seen pre-injury. Physical training in healthy animalscan greatly increase cortical representation of the muscles used, duringlearning of the task, but rehabilitative physical training in rats aftera motor cortical injury is less effective at generating this increasedrepresentation. Movement paired VNS in intact rats generates acomparable amount of cortical plasticity in approximately the sameamount of time as physical training. Movement paired VNS is also able toenhance plasticity where plasticity is not observed with training alone.Since increased cortical plasticity is related to increased functionalrecovery following cortical injury, it is possible that movement pairedVNS could enhance the recovery of specific motor functions followingcortical injury, compared to rehabilitative training alone.

Non-invasive brain stimulation techniques, such as repeated transcranialmagnetic stimulation and transcranial direct current stimulation, showpromise as methods for inducing better functional recovery withrehabilitative training following stroke than training alone. Thesetechniques apply a localized current to the scalp to manipulateelectrical fields in the cortex without the need for surgery orpharmaceuticals. These methods are thought to work primarily throughinfluencing levels of cortical excitability, but also cause increasedlevels of neurotrophic factors, serotonin, and dopamine. Combiningpaired-VNS methods with non-invasive brain stimulation may lead to evengreater recovery than either method used alone through activatingdifferent plasticity enhancing mechanisms.

Periodic VNS is Food and Drug Administration (FDA) approved as a safeand effective treatment of certain types of refractory epilepsy as wellas treatment-resistant depression. Protocols for treating epilepsycomprise about 30 seconds of VNS every about five minutes, 24 hours perday. Periodic VNS using a stimulation protocol similar to that used intreating epilepsy has improved functional recovery in rats with fluidpercussion injury to the cortex. This protocol requires about 145 timesthe daily current injection compared to what was used in the methoddisclosed herein. The above-disclosed results tend to demonstrate thatmotor and auditory events can be precisely timed with VNS to markedlyalter motor and auditory system organization, respectively. It seemslikely that therapies using paired VNS might be a more effective therapyfor increasing functional recovery following cortical damage.

Selectively pairing VNS has already shown promise in normalizingabnormal cortical organizations in the treatment of tinnitus in rats.The overrepresentation of a tone was reduced by pairing VNS with tonesspanning the rats hearing range except for the tones near the tinnitusfrequency. This eliminated the behavioral correlate of tinnitus in ratsfor several months past the cessation of the treatment. A similarstrategy of pairing VNS with movements may improve the treatment ofdisorders related to abnormal representations in the motor system, suchas dystonias. Although the causes are not fully understood, patientswith dystonia demonstrate disturbed cortical inhibition that is improvedwith the application of transcranial magnetic stimulation. Currentevidence supports that reducing the overrepresented motor area duringthese treatments is associated with a reduction in dystonic symptoms. Asdisclosed herein, the larger representations observed from the VNSpaired movements were accompanied by smaller nearby corticalrepresentations, such as movements of the head. Selectively increasingthe size of surrounding muscle representations might decrease theoverrepresentation of the dystonic muscles. Movement paired VNS ofnon-dystonic, surrounding movements may decrease the overrepresentationof the dystonic muscles. The strategic pairing of non-dystonic movementswith VNS provides a novel potential therapy to treat focal dystonia.

Clinical and pre-clinical data has been collected to support theeffectiveness of the tinnitus therapy and parameters.

Selection of the vagus nerve for stimulation is not arbitrary. The vagusnerve produces specific effects when stimulated at a specific timerelative to a physical task. The peripheral nervous system, centralnervous system including the brain and spinal cord are typically used byothers as therapeutic stimulation locations. The choice of stimulationlocation largely determines the behavioral and neurophysiologic outcome.Even though similar neural populations are activated by input from twodifferent locations, the manner in which they are activated, forexample, the pattern of activity generated within the neuron populationmay depend on the time course of activation, release of one or moreneuromodulators, attention state, etc. The neurophysiologicalconsequences therefore are bound to be different. Given the large (andunknown) number of variables that can influence the activation of agiven neural population, the mechanisms are likely to be complex andunpredictable. There is no calculus to determine which locations mayproduce which effects. Finding a location that produces a given effectcan only be done experimentally. It is not valid to suggest thatstimulation at one location makes it obvious to stimulate at a differentlocation, even if the goal is to stimulate the same population ofneurons.

The same can be said for stimulation parameters. At a given stimulationlocation, stimulation according to one set of parameters may notnecessarily produce the same (or similar) effects as a stimulationaccording to another set of parameters. The frequency of stimulation,the current amplitude of stimulation, the duration of each stimulation,the waveform of stimulation, as well as other stimulation parameters canchange the results of stimulation.

Our experiments have shown that the effect generated by VNS pairing isvery short, less than 15 seconds. A first tone at a first frequency whenpaired with VNS generated an increase in the number of neurons thatrespond to the paired frequency. A second unpaired tone at a secondfrequency, played 15 seconds after the paired VNS did not show acorresponding increase in the number of neurons that respond to thesecond frequency. Nothing in the prior art indicates this kind ofprecise timing requirement.

Similarly, we have performed experiments in which multiple tones at agiven frequency were paired with VNS and given 30 seconds apart. Thiswas done in the tinnitus study (Engineer et al., 2011) in which VNS waspaired with each of the randomly interleaved tones every 30 seconds(e.g., 1.3 kilohertz (kHz)+VNS, then wait for 30 seconds, then give 6.3kHz+VNS, and then wait for 30 seconds and so on). The tones wereselected such that they surrounded the tinnitus frequency and thetinnitus frequency itself was excluded. The idea was to shrink therepresentation of the tinnitus frequency thereby restoring the map andsynchronous activity back to normal. When the same tones were presentedeight seconds apart, the effect was less than if the tones werepresented 30 seconds apart, which was surprising.

To cite another example, we have performed a series of experiments wherea tone is repeatedly paired with a foot-shock to establish a conditionedfear response. Subsequently, when the tone was presented without afoot-shock, the rat would freeze, anticipating a foot shock. If thetone, without the foot-shock, is then presented repeatedly, the fearcaused by the tone would eventually be extinguished, undoing theconditioning. By pairing the tone (without the foot-shock) with VNS, thefear is extinguished much more quickly. However, presenting the tone byitself and then giving VNS minutes later, the fear is extinguished atthe normal rate.

Further experiments have demonstrated the effect of the describedtherapy. VNS paired with a movement improves motor performance in a ratmodel of ischemic stroke. VNS paired with movement improves a motordeficit several weeks after an ischemic lesion. VNS delivered two hoursafter rehabilitation did not show any significant difference fromrehabilitation alone.

These results demonstrate that the precise timing between VNS and theevent as well as the interval separating the VNS-event pairings appearto be important for inducing highly specific plasticity.

Neurostimulation does not behave in a predictable fashion. Differentstimulation locations produce different results, even when bothlocations are cranial nerves. For example, synchronization in thecerebral cortex is a manifestation of epilepsy. Stimulating the vagusnerve causes desynchronization of the cortex neurons, which has beenproposed as a potential mechanism for how vagus stimulation prevents anepileptic seizure. Stimulation of the trigeminal nerve, another cranialnerve, causes desynchronization as well. To determine whether theplasticity induced by VNS is specific to the vagus nerve, we pairedstimulation of the trigeminal nerve with a 19 kHz tone. However, when wepaired trigeminal stimulation with a tone, in the same way we paired VNSwith a tone, we did not observe any plasticity that was specific to thepaired tone. Pairing the trigeminal stimulation with a tone at a givenfrequency did not change the response to that frequency even though itcaused desynchronization like in the previous study. Each stimulationlocation is unique across the full range of effects. It appears that VNSmay be uniquely suited to direct cortical plasticity and suggests thatthe vagus nerve is likely a key conduit by which the autonomic nervoussystem informs the central nervous system of important stimuli.

Both VNS pairing and nucleus basalis stimulation (NBS) pairing have beenshown to change the number of neurons responding to a paired frequency.To be effective, the current amplitude parameter of the stimulation forVNS pairing is more than twice the current amplitude used for NBSpairing. There is an important difference between the neuromodulatorsreleased by NBS from those released by VNS, so significant differencesbetween the results of NBS and VNS are expected.

Another experiment demonstrated that pairing a single tone at aspecified frequency with VNS increased the number of neurons respondingnot only to that frequency but to close frequencies, e.g., increased thebandwidth compared to control rats. For NBS pairing, the bandwidth wasnot significantly different from control rats. Unlike VNS pairing, NBSpairing is highly invasive and may be unsuitable to provide a practicaltherapeutic benefit. Similar results in one circumstance cannot beextended to predict similar results in another, even slightly different,circumstance. Different stimulation parameters have to be used foreffective VNS pairing and NBS pairing.

Because of the specific neurotransmitter mechanisms that generate thespecific plasticity required for the described therapies, some drugs mayreduce the effectiveness. Muscarinic antagonists, norepinephrineblockers that are centrally acting, norepinephrine uptake inhibitors,nicotinic antagonists, Selective serotonin reuptake inhibitors, drugsthat block serotonin and drugs that block dopamine may all reduce theeffectiveness of the paired VNS therapies.

None of the description in the present application should be read asimplying that any particular element, step, or function is an essentialelement that must be included in the claim scope: the scope of patentedsubject matter is defined only by the allowed claims. Moreover, none ofthese claims is intended to invoke paragraph six of 35 U.S.C. section112 unless the exact words “means for” are followed by a participle. Theclaims as filed are intended to be as comprehensive as possible, and nosubject matter is intentionally relinquished, dedicated, or abandoned.

At least one embodiment is disclosed and variations, combinations,and/or modifications of the embodiment(s) and/or features of theembodiment(s) made by a person having ordinary skill in the art arewithin the scope of the disclosure. Alternative embodiments that resultfrom combining, integrating, and/or omitting features of theembodiment(s) are also within the scope of the disclosure. Wherenumerical ranges or limitations are expressly stated, such expressranges or limitations should be understood to include iterative rangesor limitations of like magnitude falling within the expressly statedranges or limitations (e.g., from about 1 to about 10 includes, 2, 5, 4,etc.; greater than 0.10 includes 0.11, 0.12, 0.15, etc.). For example,whenever a numerical range with a lower limit, R_(l), and an upperlimit, R_(u), is disclosed, any number falling within the range isspecifically disclosed. In particular, the following numbers within therange are specifically disclosed: R=R_(l)+k*(R_(u)−R_(l)), wherein k isa variable ranging from 1 percent to 100 percent with a 1 percentincrement, i.e., k is 1 percent, 2 percent, 5 percent, 4 percent, 5percent, . . . , 50 percent, 51 percent, 52 percent, . . . , 75 percent,76 percent, 77 percent, 78 percent, 77 percent, or 100 percent.Moreover, any numerical range defined by two R numbers as defined in theabove is also specifically disclosed. Use of the term “about” means±10%of the subsequent number, unless otherwise stated herein. Use of theterm “optionally” with respect to any element of a claim means that theelement is required, or alternatively, the element is not required, bothalternatives being within the scope of the claim. Use of broader termssuch as comprises, includes, and having should be understood to providesupport for narrower terms such as consisting of, consisting essentiallyof, and comprised substantially of. Accordingly, the scope of protectionis not limited by the description set out above but is defined by theclaims that follow, that scope including all equivalents of the subjectmatter of the claims. Each and every claim is incorporated as furtherdisclosure into the specification and the claims are embodiment(s) ofthe present disclosure. The discussion of a reference in the disclosureis not an admission that it is prior art, especially any reference thathas a publication date after the priority date of this application. Thedisclosure of all patents, patent applications, and publications citedin the disclosure are hereby incorporated by reference, to the extentthat they provide exemplary, procedural, or other details supplementaryto the disclosure.

While several embodiments have been provided in the present disclosure,it should be understood that the disclosed systems and methods might beembodied in many other specific forms without departing from the spiritor scope of the present disclosure. The present examples are to beconsidered as illustrative and not restrictive, and the intention is notto be limited to the details given herein. For example, the variouselements or components may be combined or integrated in another systemor certain features may be omitted, or not implemented.

In addition, techniques, systems, subsystems, and methods described andillustrated in the various embodiments as discrete or separate may becombined or integrated with other systems, modules, techniques, ormethods without departing from the scope of the present disclosure.Other items shown or discussed as coupled or directly coupled orcommunicating with each other may be indirectly coupled or communicatingthrough some interface, device, or intermediate component whetherelectrically, mechanically, or otherwise. Other examples of changes,substitutions, and alterations are ascertainable by one skilled in theart and could be made without departing from the spirit and scopedisclosed herein.

What is claimed is:
 1. A method, comprising: treating one or more motordeficits via the actions of: exposing a patient to a plurality oftherapeutic motions; and applying a plurality of vagus nerve stimulationelectrical pulse trains to the patient, respective trains of theplurality of trains being in temporal proximity to respectivetherapeutic motions of the plurality of therapeutic motions exposed tothe patient to improve the patient's motor deficits, wherein the pulsetrains are delivered for a period of time during at least onetherapeutic motion of the plurality of therapeutic motions, and theperiod of time has a duration that is different than a duration of theat least one therapeutic motion of the plurality of therapeutic motions.2. The method of claim 1, further comprising: detecting a respectivebeginning of the at least one therapeutic motion of the plurality oftherapeutic motions; and applying a respective vagus nerve stimulationpulse train of the plurality of pulse trains based on the detectedbeginning.
 3. The method of claim 1, further comprising: automaticallydetecting a respective beginning of the at least one therapeutic motionof the plurality of therapeutic motions; and automatically applying arespective vagus nerve stimulation pulse train of the plurality of pulsetrains based on the detected beginning.
 4. The method of claim 1,further comprising: selecting a therapeutic task level for the at leastone therapeutic motion of the plurality of therapeutic motions.
 5. Themethod of claim 1, wherein the pulse trains are no longer than about 500milliseconds in duration.
 6. The method of claim 1, wherein the actionof applying a plurality of vagus nerve stimulation pulse trains to thepatient entails operating an implanted neurostimulator to deliver pulsetrains of electrical stimulation energy to the vagus nerve such that arespective pulse train results in respective directed neuro plasticitylasting no more than about 8 seconds.
 7. The method of claim 1, whereinthe action of applying a plurality of vagus nerve stimulation pulsetrains to the patient further comprises sensing respective performancesof the selected therapeutic motions and applying the pulse trains to thevagus nerve based on the sensed beginnings of the performances.
 8. Amethod, comprising: treating one or more motor deficits via the actionsof: selecting one or more therapeutic motions; repetitively performingone or more therapeutic motions of the selected therapeutic motions; andpairing a respective vagus nerve electrical stimulation pulse train witha respective therapeutic motion of the performed plurality oftherapeutic motions, thereby improving the patient's motor deficits,wherein the respective vagus nerve stimulation pulse train is deliveredfor a period of time during the respective therapeutic motion, and theperiod of time has a duration that is less than a duration of therespective therapeutic motion.
 9. The method of claim 8, wherein: theaction of selecting one or more therapeutic motions includes selecting aplurality of therapeutic motions; and the action of repetitivelyperforming the one or more therapeutic motions includes repetitivelyperforming the plurality of therapeutic motions.
 10. The method of claim8, further comprising: determining that a key portion of a therapeuticmotion of the performed therapeutic motions is occurring; and applying arespective vagus nerve stimulation pulse train of the plurality of pulsetrains based on the determined occurrence of the key portion.
 11. Themethod of claim 10, wherein: the key portion occurs after a beginning ofthe therapeutic motion.
 12. The method of claim 8, further comprising:automatically determining that a key portion of a therapeutic motion ofthe performed therapeutic motions is occurring; and applying arespective vagus nerve stimulation pulse train of the plurality of pulsetrains based on the determined occurrence of the key portion.
 13. Themethod of claim 8, further comprising: selecting a therapeutic tasklevel for at least the repetitively performed one or more therapeuticmotions.
 14. The method of claim 13, further comprising: changing thetherapeutic task level between the repetitively performed one or moretherapeutic motions.
 15. The method of claim 8, wherein the action ofpairing the respective vagus nerve stimulation pulse train to therespective therapeutic motion further comprises operating an implantedneurostimulator to deliver pulse trains of electrical stimulation energyto the vagus nerve such that a respective pulse train results inrespective directed neuro plasticity lasting no more than about 8seconds.
 16. A method, comprising: treating one or more motor deficitsvia the actions of: selecting one or more therapeutic motions;repetitively exposing the patient to the one or more therapeuticmotions; and applying a plurality of electrical vagus nerve stimulationpulse trains to the patient, respective trains of the plurality oftrains being in temporal proximity to respective therapeutic motionsexposed to the patient to improve the patient's motor deficits, whereinthe pulse trains are delivered for a period of time during at least onetherapeutic motion of the one or more therapeutic motions, and theperiod of time has a duration that is less than a duration of the atleast one therapeutic motion of the one or more therapeutic motions. 17.The method of claim 16, wherein: the action of selecting one or moretherapeutic motions includes selecting a plurality of therapeuticmotions; and the action of repetitively performing the one or moretherapeutic motions includes repetitively performing the plurality ofmotions.
 18. The method of claim 16, further comprising the action ofsensing beginnings of respective performances of the selectedtherapeutic tasks and applying the pulse trains to the vagus nerve basedon the sensed beginnings of the performances.
 19. The method of claim16, wherein the pulse trains have a current of no less than about 0.8milliamperes.
 20. The method of claim 16, further comprising sensingrespective performances of the selected therapeutic task, and applyingthe pulse trains to the vagus nerve based on the sensed performances.21. The method of claim 16, wherein the action of applying the pluralityof vagus nerve stimulation pulse trains to the patient further comprisesoperating an implanted neurostimulator to deliver pulse trains ofelectrical stimulation energy to the vagus nerve such that a pulse trainresults in respective directed neuro plasticity lasting no more thanabout 8 seconds.
 22. A method, comprising: treating one or more motordeficits via the actions of: applying vagus nerve stimulation and motortherapy to a patient, thereby reorganizing a motor cortex of the patientand thus treating the one or more motor deficits, wherein the vagusnerve stimulation comprises at least one electrical pulse traindelivered for a period of time during at least one therapeutic motionassociated with the motor therapy, the at least one therapeutic motionis one or more of performed by the patient or a movement to which thepatient is exposed, and the period of time is a portion of a duration ofthe at least one therapeutic motion, wherein the portion of the periodof time is different from the duration.
 23. The method of claim 22,wherein: the motor therapy includes a specific motion action; and theapplied vagus nerve stimulation and motor therapy increases a corticalrepresentation of the specific motion action relative to that whichwould be the case in the absence of applying the vagus nervestimulation.
 24. The method of claim 23, wherein: the temporallycontrolled manner includes a controlled temporal correlation betweenrespective vagus nerve stimulations and respective repetitive actions ofthe motor therapy.
 25. The method of claim 22, wherein: applied vagusnerve stimulation and motor therapy increases a cortical plasticity,thereby treating the one or more motor deficits.
 26. The method of claim22, wherein: the applied vagus nerve stimulation and motor therapygenerates a cortical plasticity, thereby treating the one or more motordeficits.
 27. The method of claim 22, wherein: the motor therapyincludes a specific motion action; and the applied vagus nervestimulation and motor therapy generates a cortical plasticity specificto the specific motion action, thereby treating the one or more motordeficits.
 28. The method of claim 22, wherein: the action ofreorganizing the motor cortex includes generating directed plasticity ofthe cortex by applying the vagus nerve stimulation in a temporallycontrolled manner.